Rett syndrome (RTT) is a severe neurological disorder causing progressive loss of motor and language skills in girls. Mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2) and the loss of MeCP2 function in the brain are the primary cause of RTT. Mecp2-knockout (Mecp2-null) mice and those with truncated MeCP2 recapitulate many features of RTT, and the phenotype in these mice is caused by MeCP2 deficiency in the brain. The lack of change in brain cytoarchitecture in RTT patients and MeCP2 mutant mice suggests that subtle changes in neuronal and synaptic functions are the primary cause. MeCP2 is highly expressed in both excitatory and inhibitory neurons in the brain. While recent studies have demonstrated a key role for MeCP2 in excitatory transmission, little is known about the role of MeCP2 in the development and function of inhibitory synapses. Our preliminary studies demonstrated that GABAergic transmission is significantly altered in the thalamus of Mecp2-null mice. Most interestingly, we found that GABAergic transmission is altered in opposite directions in excitatory and inhibitory neurons. We hypothesize that MeCP2 plays an important role in the development of GABAergic synapses in the thalamus. We will examine this hypothesis using a combination of electrophysiology, anatomy, and immuno- histochemistry in Mecp2-null mice. The two specific aims are to 1) determine changes in GABAergic transmission in the thalamus of Mecp2-null mice during postnatal development;and 2) determine structural basis for GABAergic defects in the thalamus. PUBLIC HEALTH RELEVANCE: This research will advance our understanding of the pathogenesis of Rett syndrome, and may provide opportunity for the development of new and improved treatments.